A mild case of nesidioblastosis with diagnostic and therapeutic difficulty

A female infant with nesidioblastosis who showed mild clinical symptoms is reported. In this patient, insulin levels and insulin to glucose ratios (IRI/G) were often normal. Regular milk feedings supplemented with continuous glucose infusion (0.7-2 mg/kg per min) or oral glucose feedings (4.5 mg/kg per min) prevented hypoglycemia. As leucine-sensitivity was diagnosed at 2 months of age, she was started on diazoxide. This was, however, ineffective, and adverse effects appeared. Subtotal pancreatectomy (95%) was therefore attempted at 5 months of age, and persistent normoglycemia as well as normal growth and development followed up to 3 years after the operation. The pancreas showed characteristic signs of nesidioblastosis. The above clinical observation suggests that a patient with nesidioblastosis whose blood glucose level is easily controllable may develop an unexpected episode of hypoglycemia in the presence of a leucine sensitivity. In such a patient, diazoxide or, when it is of no avail, surgical intervention should promptly be instituted to prevent possible neurologic sequelae induced by hypoglycemia.     

The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.     

Successful Catheter Ablation of Reentrant Junctional Tachycardia in a Patient with Asplenia Syndrome before Total Cavo‐Pulmonary Connection

Asplenia syndrome is commonly associated with complex structural cardiac malformations, and junctional tachycardia (JT), which may compromise hemodynamic status, has been reported in association with asplenia syndrome. 1 We report successful radiofrequency catheter ablation of reentrant JT in a patient with asplenia syndrome. (PACE 2010; e43–e45)     

Electron microscopic finding of eccrine sweat gland epithelial cells in a patient with Krabbe disease

A 13 month old boy was found to have severely reduced β-galactocerebrosidase activity suggesting infantile Krabbe disease. Clinically, the patient showed a progressive neurological deterioration with white-matter disease on radiological study. Axillary skin biopsy was performed to support the diagnosis. On electron microscopy, needle-like inclusions, which are the typical finding seen in the cytoplasm of astrocytes and Schwann cells in the classic infantile form, were present in eccrine sweat gland epithelial cells. This method is useful for diagnosis when nerve biopsy and biochemical analysis are not readily available.     

Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients

Hasegawa T, Okamoto A, Kamimura T, Tatsuno I, Hashikawa S‐N, Yabutani M, Matsumoto M, Yamada K, Isaka M, Minami M, Ohta M. Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients. APMIS 2010; 118: 167–78. Streptococcal toxic shock syndrome (STSS) is a re‐emerging infectious disease in Japan and many other developed countries. Epidemiological studies have revealed that the M1 serotype of Streptococcus pyogenes is the most dominant causative isolate of STSS. Recent characterization of M1 isolates revealed that the mutation of covS, one of the two‐component regulatory systems, plays an important role in STSS by altering protein expression. We analyzed the M1 S. pyogenes clinical isolates before or after 1990 in Japan, using two‐dimensional gel electrophoresis (2‐DE) and pulsed‐field gel electrophoresis (PFGE). PFGE profiles were different between the isolates before and after 1990. Markedly different profiles among isolates after 1990 from STSS and pharyngitis patients were detected. Sequence analysis of two‐component regulatory systems showed that covS mutations were detected not only in STSS but also in three pharyngitis isolates, in which proteins from the culture supernatant displayed the invasive type. The mutated CovS detected in the pharyngitis isolates had impaired function on the production of streptococcal pyrogenic exotoxin B (SpeB) analyzed by 2‐DE. These results suggest that several covS mutations that lead to the malfunction of the CovS protein occurred even in pharyngeal infection.     

Conduction Delay in Right Ventricle as a Marker for Identifying High‐Risk Patients With Brugada Syndrome

Conduction Delay as a Marker for Brugada Syndrome. Objectives: To evaluate the significance of conduction delay (CD) in the right ventricle (RV) in Brugada syndrome (BS) as a marker for risk stratification of sudden death. Methods: Twenty‐five patients with BS (7 with documented ventricular fibrillation (VF), 8 with syncope, and 10 without symptoms) and 10 control subjects were paced from the RV apex using 8 beats of drive pacing and a single extra‐stimulus. CDs in the right ventricular outflow tract (RVOT) (CD‐RV) and in the lateral left ventricle (L‐LV) (CD‐LV), and the local electrogram durations at a single extra‐stimulus in RVOT (D‐RV) and L‐LV (D‐LV) were calculated. We also evaluated changes in 12‐lead ECG parameters in 16 patients with BS after pilsicainide challenge test (Pilsicainide‐test). Results: Maximal CD‐RV and maximal D‐RV were significantly larger than maximal CD‐LV and maximal D‐LV in BS (26 ± 10 and 105 ± 15 vs 20 ± 6 and 92 ± 15 ms, P < 0.05, respectively). Maximal CD‐RV and maximal D‐RV in patients with documented VF were the largest among the 3 groups. There was a significant positive correlation between maximal CD‐RV or maximal D‐RV and changes in QRS duration in leads V2 and V5 and in S wave duration in lead II and V5 after Pilsicainide‐test (CD‐RV; r = 0.54, 0.51, 0.56, and 0.53: D‐RV; r = 0.55, 0.5, 0.57, and 0.53, P < 0.05, respectively). In control subjects, there were no significant differences. Conclusions: CD in RV was a useful marker for identifying high‐risk patients with BS. CD in the RV, especially in the RVOT epicardium, may be related to arrhythmias in BS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 688‐696, June 2010)     

ETHANOL INDUCES TRANSIENT ARREST OF CELL DIVISION (G2 + M BLOCK) FOLLOWED BY G0/G1 BLOCK: DOSE EFFECTS OF SHORT- AND LONGER-TERM ETHANOL EXPOSURE ON CELL CYCLE AND CELL FUNCTIONS

To study the cytophysiological effects of ethanol systematically,L929 cells, a fibroblastic cell line derived from mouse connectivetissue, were exposed to various concentrations of ethanol (12.5,50, 100 and 200 mM) for short (3 and 6 h) and longer (24 or26 h) durations. Ethartol-induced cellular responses were analysedby a combination of the following assays: number of cells, amountsof DNA and protein, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide) assay and cell cycle. Ethanol dose-dependently suppressedthese cellular functions, except that 12.5 mM exposures forboth 6 and 26 h increased the amount of protein in spite ofalmost no change in other cellular functions, compared to thecontrol. The most marked dose-dependency was observed in a reductionof formazan product in an MTT assay after both 6 and 26 h exposuresto ethanol, being independent of the number of cells and probablyreflecting dose-dependent depression of mitochondrial respiration.A G₂+M block in the cell cycle, an inhibition of cell division,was induced after short-term exposures (3 and 6 h) to 100 and200 mM ethanol, but the block was released before 24 h had passed.Alternatively, prolonged exposures (24 h) to 50–200 mMethanol induced a G₀/G₁ block, resulting in a decrease in theamount of DNA below the control value. Moreover, the percentageof the S phase was decreased gradually and dose-dependentlythroughout the 24 h exposure. Thus, high concentrations of ethanol(50, 100 and 200 mM) perturbed the cell cycle progression bycausing both a transient G₂+M block (an inhibition of mitosis)and a continuous G₀/G₁ block, though the latter was masked bythe G₂+M block during shortterm exposure. The cells seem finallyto acquire some tolerance to ethanol so as to pass through mitosis,but much less tolerance to pass through the checkpoint fromthe G₁ to the S phase, which results in a decline in proliferation.